11 - [ (Z) -3- (Dimethylamino) Propylidene] - 6, 11-Dihydro-Dibenz [B,E] Oxepin-2-Yl] - Acetic Acid

Inactive Publication Date: 2009-01-01
URQUIMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Until now, all processes described for the preparation of olopatadine have some disadvantages for their application at industrial scale.

Method used

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  • 11 - [ (Z) -3- (Dimethylamino) Propylidene] - 6, 11-Dihydro-Dibenz [B,E] Oxepin-2-Yl] - Acetic Acid
  • 11 - [ (Z) -3- (Dimethylamino) Propylidene] - 6, 11-Dihydro-Dibenz [B,E] Oxepin-2-Yl] - Acetic Acid
  • 11 - [ (Z) -3- (Dimethylamino) Propylidene] - 6, 11-Dihydro-Dibenz [B,E] Oxepin-2-Yl] - Acetic Acid

Examples

Experimental program
Comparison scheme
Effect test

example 1

[3-Formyl-4-(2-iodo-benzyloxy)-phenyl]-acetic Acid Methyl Ester

[0053]A solution of (3-formyl-4-hydroxy-phenyl)-acetic acid methyl ester (17.2 g, 85.9 mmol) in acetonitrile was slowly added to a solution of 1-chloromethyl-2-iodo-benzene (13.06 g, 94.5 mmol) and Nal (3.22 g, 21.5 mmol) in acetonitrile (273 ml) at reflux temperature and the mixture was mantained at this temperature for 3 hours. Once the mixture reached room temperature, the residue that had formed was filtered, washed with acetonitrile and concentrated to obtain a residue that was then dissolved in toluene (330 ml) and washed with NaOH 0.1N and water. The organic layer was concentrated to dryness, diluted with acetone (330 ml) and was stirred into water (500 ml) at room temperature. The mixture was filtered and washed with water to obtain 33.959 (96%) of [3-Formyl-4-(2-iodo-benzyloxy)-phenyl]-acetic acid methyl ester, which was purified by crystallization in toluene-cyclohexane (99% HPLC)

[0054]1H-RMN (300 MHz, CDCl3): ...

example 2

[4-(2-Formyl-benzyloxy)-3-iodo-phenyl]-acetic Acid Methyl Ester

[0055]2-Bromomethyl-benzaldehyde (11 g, 55.26 mmol) in acetonitrile (132 ml) was added to a solution of (4-Hydroxy-3-iodo-phenyl)-acetic acid methyl ester (16.06 g, 55 mmol), K2CO3 (8.36 g, 60.50 mmol) and Nal (2.07 g, 13.80 mmol) in acetonitrile (88 ml). The mixture was heated to reflux temperature and was stirred at this temperature for 3 hours. Once the mixture cooled down to room temperature, it was filtered and was then concentrated to dryness to obtain a residue that was diluted in toluene (212 ml) and then it was washed with NaOH 0.05N. Once the layers had separated, the aqueous layer was washed with toluene (100 ml) again and the organic layers were washed with water (2×100 ml, 1×50 ml), were concentrated to dryness to obtain a residue, which was then diluted with a mixture of acetone-water at 30° C. Then the mixture was cooled until 20-22° C. The solid formed was filtered to obtain 18 g (80%) of [4-(2-Formyl-ben...

example 3

(E)-[3-(4-Dimethylamino-but-1-enyl)-4-(2-iodo-benzyloxy)-phenyl]-acetic Acid Methyl Ester

[0057]Lithium bis(trimethylsilyl)amide (LiHMDS) (1M THF, 51.5 ml, 51.5 mmol) was added drop by drop to a dispersion of (3-Dimethylamino-propyl)-triphenyl-phosphonium iodide (24.33 g, 51.2 mmol) in anhydrous toluene (300 ml) at room temperature and in an inert atmosphere. The mixture was stirred at this temperature for 1 hour. Following this a solution of and [3-Formyl-4-(2-iodo-benzyloxy)-phenyl]-acetic acid methyl ester (5 g, 12.2 mmol) in anhydrous toluene was added to the mixture and they were stirred at room temperature for 2 h 30 min. Hydrochloric acid 2N was added to the mixture and organic layers were washed by HCl 2N. Aqueous layers were washed with toluene and then they were alkalized with K2CO3. Aqueous layers were extracted with ethyl acetate, filtered, dried and concentrated to dryness to obtain 4.74 g (83%) of [3-(4-Dimethylamino-but-1-enyl)-4-(2-iodo-benzyloxy)-phenyl]-acetic acid ...

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PUM

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Abstract

Process for the preparation of olopatadine (I), which comprises reacting a compound of formula (V) in the presence of a palladium catalyst to, provide a compound of formula (VI), wherein the acid protecting group is removed to provide the compound of formula (I) and if desired, transformation into its salts.

Description

[0001]This application is a 371 filing of PCT / EP2005 / 007501, filed Jul. 11, 2005 which claims priority to Spanish Application No. 200401864, filed Jul. 28, 2004. These prior applications are incorporated herein by reference.[0002]The present invention provides a new process for the preparation of 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-yl]-acetic acid useful as an antihistaminic agent, and its intermediates of the synthesis.DESCRIPTION OF THE TECHNICAL STATUS[0003]The compound of 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-yl]-acetic acid represented by formula I, commonly known as Olopatadine, has been used as an active constituent drug, in form of its hydrochloride salt.[0004]The preparation of the compound of formula I has been described previously in U.S. Pat. No. 5,115,883 and U.S. Pat. No. 4,871,865, where it is prepared from the basic structure dibenzo[b,e]oxepine-11-one (formula II) suitably substituted,where R is CH2...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D313/12
CPCC07C69/734C07C69/738C07D313/12C07C229/34C07C217/48Y02P20/55
Inventor BOSCH CARTES, JOANBACHS ROCA, JORDIGOMEZ GOMEZ, ANTONIA MAALONSO MARIN, YOLANDABESSA SANCHEZ, MERCE
Owner URQUIMA
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